We have identified a new class of pathogen-associated molecular pattern (PAMP) proteins (deoxyuridine triphosphate nucleotidohydrolases; dUTPases) that have novel immunoregulatory and neuroregulatory functions that may contribute to the pathophysiology of diseases caused by human herpesviruses. Using the Epstein-Barr virus (EBV)- dUTPase as the prototype, our pioneering studies have demonstrated conclusively that the EBV-dUTPase induces sickness and anxiety behavior and impaired learning/memory effects independent of its enzymatic activity. Furthermore, the properties of the EBV- dUTPase were enhanced by stress. This multidisciplinary research grant will provide new information on the mechanism by which stress can impact the EBV-dUTPase-mediated effects as it relates to chronic fatigue syndrome.